The present invention relates to a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
1. Background of the Invention
Myotonia, which seriously restrains daily life, is induced by any of a number of factors or a combination thereof, for example, cervico-omo-brachial syndromes accompanying stiffness or pain in the neck, shoulder, arm, lumbar and dorsal skeletal muscles due to abnormal posture, fatigue, changes in the backbone with ageing etc., shoulder periarthritis accompanying inflammation in the tissues constituting the shoulder joint due to changes in the shoulder joint caused by trauma, etc., and spastic paralysis wherein accelerated limb muscle tonus hinders voluntary movements.
In particular, spastic paralysis is a disease which accompanies limb muscle tonus, stiffening, walking difficulty, etc. and thus seriously restrains daily life.
2. Prior Art
It has been a practice to treat these diseases mainly with the use of medicaments. At the present stage, central muscle relaxants or peripheral muscle relaxants are administered to patients with these diseases.
Particular examples of used central muscle relaxants include Tolperisone hydrochloride, Baclofen, Tizanidine hydrochloride, Chlorzoxazone and Diazepam.
On the other hand, particular examples of used peripheral muscle relaxants include suxamethonium chloride, Pancuronium bromide and dantrolene sodium.
Central muscle relaxants act selectively on the central nervous system so as to relax muscles. Therefore, it is expected that those action on the upper center would exhibit a more potent muscle relaxant effect. However, there arise at the same time some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness and atony. Namely, there has been known hitherto no medicament capable of achieving well-balanced principal action and side effects.
Diazepam, which is inherently a minor tranquilizer, is efficacious against diseases accompanying mental symptoms such as anxiety, tension and depression. However, its effect is too potent to merely ameliorate myotonia. With the use of diazepam, therefore, spastic paralysis can be relieved but there arise some problems such as dizziness.
On the other hand, suxamethonium chloride and Pancuronium bromide which are peripheral muscle relaxants are marketed exclusively as injections, which makes the chronic administration thereof difficult.
Dantrolene sodium is processed into injections and preparations for oral use and has a relatively potent muscle relaxant effect. However, it suffers from problems of having only a low margin of safety and frequently inducing muscular atony. Accordingly, it is difficult for those other than medical specialists to administer this medicine.
As discussed above, there has been known hitherto no medicaments for treating and ameliorating myotonia in spastic paralysis etc., which is clinically useful and has a high safety.
Under these circumstances, the present inventors have conducted extensive studies to develop medicaments for treating, ameliorating and preventing spastic paralysis or central muscle relaxants which have a potent effect of ameliorating myotonia while sustaining a high safety and newly paid their attention to compounds having a serotonin antagonism. As a result, they have successfully found that a novel condensed pyridine compound represented by the following formula or a pharmacologically acceptable salt thereof has an excellent central muscle relaxant effect and a high safety and thus makes it possible to solve the above problems, thus completing the present invention.
Accordingly, the present invention aims at providing clinically useful novel medicaments which have well-balanced principal action and side effects and make it possible to overcome the problem encountering in the prior art that those acting on the upper center would exhibit a more potent muscle relaxant effect but at the same time suffer from some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness and weakness.
Because of the anti-serotonin effect, it is expected that the condensed pyridine compound of the present invention is moreover usable in preventing, treating and ameliorating depression, emotional disorders, schizophrenia, sleep disturbance, anxiety, spinal cord injury, thrombosis, hypertension, brain circulatory disturbances, peripheral circulatory disturbances, drug addiction, etc.
In addition to the condensed pyridine compound, the present invention provides medicinal composition which comprises a pharmaceutically effective dose of the condensed pyridine compound, its pharmaceutically acceptable salt or hydrates thereof and pharmaceutically acceptable carriers. Further, it provides an agent for treating, ameliorating or preventing diseases against which serotonin antagonism is efficacious, an agent for treating, ameliorating or preventing spastic paralysis and a muscle relaxant, which comprise the above-mentioned active ingredient.
Further, it provides a treating, ameliorating or prophylactic agent comprising the above-mentioned effective ingredient for diseases for which the serotonin antagonism is efficacious or , a therapeutic, ameliorating and prophylactic agents of spastic paralysis and a muscle relaxation agent.
Furthermore, it provides a method for treating diseases against which the serotonin antagonism is efficacious or spastic paralysis, or ameliorating myotonia, which comprising the step of administering a pharmacologically effective dose of the condensed pyridine compound, its pharmacologically acceptable salt or hydrates thereof to a patient. Additionally, it provides the use of the effective ingredient for producing the above-mentioned medicaments.
Herein, the condensed pyridine compound (I) of the present invention is represented by the following formula: 
wherein, ring A represents benzene ring, pyridine ring, thiophene ring or furan ring;
R1 represents hydrogen atom, halogen atom, a lower alkyl group or a lower alkoxyl group;
R2represents 4-morpholinyl group, 1-imidazolyl group, 1-lower alkyl homopiperazin-4-yl group or any one selected from the groups represented by the following formulae: 
xe2x80x83(wherein, T represents nitrogen atom or methine group;
R3 represents hydrogen atom, halogen atom, a lower alkyl group or a lower alkoxyl group;
R4 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an aryl group, an aralkyl group, 1-piperidyl group, an alkenyl group, a cyano lower alkyl group, a carbamoyl lower alkyl group, a lower acyl group, an aromatic acyl group, a lower alkoxyl carbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group;
R5 and R6 are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a di lower alkyl aminoalkyl group, an optionally substituted heteroaryl lower alkyl group);
n represents 0 or an integer of 1 to 6; and
B represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyloxy group, an aryl(hydroxy)alkyl group, an aromatic acyl amino group, an arylsulfonylamino group, a lower alkoxyl arylsulfonylamino group, a hydroxy lower alkoxyl styryl group, a lower alkoxyl aryloxy group, 4-phenylpiperidin-1-yl group, 4-pyridylpiperidin-1-yl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroarylalkenyl group, an optionally substituted heteroarylalkynyl group, an aromatic acyl alkynyl group, an optionally N-substituted amino lower alkyl group, an optionally substituted arylamino group, an optionally substituted aralkylamino group or any one selected from the groups represented by the following formulae: 
xe2x80x83(wherein z represents 0 or 1;
Q represents nitrogen atom or methine group;
R7, R8 and R9 are the same as or different from each other and each represents hydrogen atom, halogen atom, hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxyl group, a lower thioalkoxyl group, a hydroxy lower thioalkoxyl group, an arylthio group, a heteroarylthio group, a heteroaryl(hydroxy)alkyl group, a halogenated lower alkyl group, a hydroxy lower alkyl group, a dihydroxy lower alkyl group, a halogenated (hydroxy) lower alkyl group, a hydroxyalkenyl group, a hydroxyalkynyl group, a hydroxy lower cycloalkenyl group, a lower alkoxy(hydroxy)alkyl group, a lower alkoxy(hydroxy)alkoxy group, a lower alkoxyalkyl group, a lower alkoxyalkoxy group, a lower thioalkoxyalkoxy group, a lower alkylsulfonylalkoxy group, a hydroxy lower alkoxy group, a dihydroxy lower alkoxy group, a hydroxy lower alkylalkoxy group, a hydroxyimino lower alkyl group, a lower cycloalkyl (hydroxy) alkyl group, an aralkyl group, a hydroxyaralkyl group, cyano group, a cyano lower alkyl group, amide group (carbamoyl group), an N-lower alkylamide group, an N-lower cycloalkylamide group, an N,N-di lower alkylamide group, an N-hydroxy lower alkylamide group, an N-hydroxy lower alkyl-N-lower alkylamide group, an N-arylamide group, cyclic aminocarbonyl group, carbamoyl group, an N-lower alkyl carbamoyl group, an N,N-di lower alkyl carbamoyl group, aminosulfonyl group, cyclic aminosulfonyl group, an N-lower alkylaminosulfonyl group, an N-lower cycloalkylaminosulfonyl group, an N,N-di lower alkylaminosulfonyl group, an N-hydroxy lower alkylaminosulfonyl group, an N-lower alkoxyalkylaminosulfonyl group, an N-halogenated lower alkylsulfonyl group, pyrrolidinylsulfonyl group, a lower alkylsulfonylaminoalkyl group, an N-lower alkylaminosulfonylalkyl group, an N,N-di lower alkylaminosulfonylalkyl group, a lower acyl group, a lower acylalkyl group, a lower cycloalkyl (hydroxy) methyl group, tetrahydropyranyl group, hydroxytetrahydropyranyl group, a hydroxy lower alkyltetrahydropyranyl group, a lower acylaminoalkyl group, (thiazol-2-yl)hydroxymethyl group, di(thiazol-2-yl)hydroxymethyl group, a lower alkylsulfonyl group, a lower alkoxyalkylsulfonyl group, a hydroxy lower alkylsulfonyl group, a lower alkylsulfonylalkyl group, an N-lower alkylamidealkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaryl lower alkyl group, a heteroaryl lower alkoxy group, a heteroarylsulfonyl group, 4-morpholinylsulfonyl group, 4-oxythiomorpholinylsulfonyl group, 4-dioxythiomorpholinylsulfonyl group, 4-morpholinylsulfonyl group, a hydroxy lower cycloalkyl group, a hydroxy lower cycloalkyloxy group, a hydroxycycloalkenyl group, a halogenated hydroxy lower alkyl group, 4-hydroxypiperidyl group, a 4-lower alkoxypiperidyl group, an xcfx89,xcfx89-lower alkylenedioxyalkyl group, an xcfx89,xcfx89-lower alkylenedioxyalkoxy group, a lower cycloalkylhydroxymethyl group, an aryloxy group, an arylaminosulfonyl group, amino group, a lower alkylamino group, a di lower alkylamino group, a hydroxy lower alkylamino group, a lower acylamino group, a hydroxy lower acylamino group, a lower alkylsulfonylamino group, a pyridyl lower alkoxy group, a lower alkylpyridylalkoxy group, a lower alkoxyhydroxyalkoxy group, a lower thioalkoxyalkoxy group, a lower alkylsulfonylalkoxy group, an N-lower alkylcarbamoyl group, an N,N-di lower alkylcarbamoyl group, an N-hydroxy lower alkylcarbamoyl group, an N-hydroxy lower alkyl -N-lower alkylcarbamoyl group, a halogenated lower alkoxy group, a cyano lower alkoxy group, a hydroxy lower cycloalkoxy group, trifluoromethyl group, trifluoromethoxy group, an amino lower alkoxy group, an N-lower alkyl aminoalkoxy group, an N,N-di lower alkylaminoalkoxy group, a lower acylalkoxy group, a lower acylaminoalkoxy group, a (1,3-dioxolanyl) lower alkyl group, a (1,3-dioxolanyl) lower alkoxyl group, an amide lower alkoxyl group, a 4-(hydroxyalkyl) tetrahydropyran-4-yl group, 2,3-dihydrobenzofuranyl group, a 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl group, indanonyl group, hydroxyindanyl group, an imidazolyl lower alkoxyl group, succinimide group or 2-oxazolidon-3-yl group;
furthermore, R7 represents hydrogen atom, while R8 and R9 form cyclopentanone ring, hydroxycyclopentane ring, a hydroxyalkylcyclopentane ring, cyclohexanone ring, hydroxycyclohexane ring, a hydroxyalkylcyclohexane ring, 2-hydroxymethyl-2-methylcyclopentanone ring, 1,2-ethylenedioxy ring or methylenedioxy ring;
m or p represents 0 or an integer of 1 to 6;
R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R25, R27 and R29 independently represent hydrogen atom, halogen atom, hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group or tetrahydropyranyl group;
R11 represents hydrogen atom, halogen atom, hydroxy group, a lower alkyl group or a lower alkoxy group;
R24 represents hydrogen atom or a lower alkyl group;
R26 represents hydrogen atom or a hydroxy lower alkyl group;
R28 represents hydrogen atom or a lower alkyl group;
R30 represents hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group or a hydroxy lower alkoxy group;
W represents sulfur atom or oxygen atom;
the bond represented by the following formula:
- - - - -
xe2x80x83represents a single or double bond; and
the bond represented by the following formula: 
xe2x80x83represents trans or cis bond.).
Among these condensed pyridine compounds, the condensed pyridine compound (II) represented by the following formula is more preferable: 
wherein, ring A represents benzene ring, thiophene ring or furan ring;
R1 represents hydrogen atom, halogen atom, a lower alkyl group or a lower alkoxy group;
R2 represents 4-morpholinyl group, 1-imidazolyl group, a 1-lower alkylhomopiperazin-4-yl group or any one selected from the groups represented by the following formulae: 
xe2x80x83(wherein, T represents nitrogen atom or methine group;
R4 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an aryl group, an aralkyl group, 1-piperidyl group, an alkenyl group, a cyano lower alkyl group, a carbamoyl lower alkyl group, a lower acyl group, an aromatic acyl group, a lower alkoxy carbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group; and
R5 and R6 are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a di lower alkylaminoalkyl group, an optionally substituted heteroaryl lower alkyl group.);
n represents 0 or an integer of 1 to 6; and
B represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyloxy group, an aryl(hydroxy)alkyl group, an aromaticacylamino group, an arylsulfonylamino group, a lower alkoxyarylsulfonylamino group, a hydroxy lower alkoxystyryl group, a lower alkoxyaryloxy group, 4-phenylpiperidin-1-yl group, 4-pyridylpiperidin-1-yl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroarylalkenyl group, an optionally substituted heteroarylalkynyl group, an aromaticacylalkynyl group, an optionally N-substituted amino lower alkyl group, an optionally substituted arylamino group, an optionally substituted aralkylamino group or any one selected from the groups represented by the following formulae: 
xe2x80x83(wherein, z represents 0 or 1;
Q represents nitrogen atom or methine group;
R7, R8 and R9 are the same as or different from each other and each represents hydrogen atom, halogen atom, hydroxy group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower thioalkoxy group, a hydroxy lower thioalkoxy group, an arylthio group, a heteroarylthio group, a heteroaryl(hydroxy)alkyl group, a halogenated lower alkyl group, a hydroxy lower alkyl group, a dihydroxy lower alkyl group, a halogenated(hydroxy) lower alkyl group, a hydroxyalkenyl group, a hydroxyalkynyl group, a hydroxy lower cycloalkenyl group, a lower alkoxy(hydroxy)alkyl group, a lower alkoxy(hydroxy) alkoxy group, a lower alkoxyalkyl group, a lower alkoxyalkoxy group, a lower thioalkoxyalkoxy group, a lower alkyl sulfonylalkoxy group, a hydroxy lower alkoxy group, a dihydroxy lower alkoxy group, a hydroxy lower alkylalkoxy group, a hydroxyimino lower alkyl group, a lower cycloalkyl (hydroxy) alkyl group, an aralkyl group, a hydroxyaralkyl group, cyano group, a cyano lower alkyl group, amide group (carbamoyl group), an N-lower alkyl amide group, an N-lower cycloalkyl amide group, an N,N-di lower alkyl amide group, an N-hydroxy lower alkyl amide group, an N-hydroxy lower alkyl-N-lower alkyl amide group, an N-arylamide group, a cyclic amino carbonyl group, carbamoyl group, an N-lower alkyl carbamoyl group, an N,N-di-lower alkyl carbamoyl group, aminosulfonyl group, a cyclic amino sulfonyl group, an N-lower alkyl aminosulfonyl group, an N-lower cycloalkylaminosulfonyl group, an N,N-di lower alkyl aminosulfonyl group, an N-hydroxy lower alkylaminosulfonyl group, an N-lower alkoxyalkylaminosulfonyl group, an N-halogenated lower alkylsulfonyl group, pyrrolidinylsulfonyl group, a lower alkylsulfonylaminoalkyl group, an N-lower alkylaminosulfonylalkyl group, an N,N-di lower alkylaminosulfonylalkyl group, a lower acyl group, a lower acylalkyl group, a lower cycloalkyl(hydroxy)methyl group, tetrahydropyranyl group, hydroxytetrahydropyranyl group, a hydroxy lower alkyltetrahydropyranyl group, a lower acylaminoalkyl group, (thiazol-2-yl)hydroxymethyl group, di(thiazol-2-yl)hydroxymethyl group, a lower alkylsulfonyl group, a lower alkoxyalkylsulfonyl group, a hydroxy lower alkyl sulfonyl group, a lower alkyl sulfonylalkyl group, an N-lower alkyl amidealkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaryl lower alkyl group, a heteroaryl lower alkoxy group, a heteroarylsulfonyl group, 4-morpholinylsulfonyl group, 4-oxythiomorpholinylsulfonyl group, 4-dioxythiomorpholinylsulfonyl group, 4-morpholinylsulfonyl group, a hydroxy lower cycloalkyl group, a hydroxy lower cycloalkyloxy group, a hydroxycycloalkenyl group, a halogenated hydroxy lower alkyl group, 4-hydroxypiperidyl group, a 4-lower alkoxy piperidyl group, an xcfx89,xcfx89-lower alkylene dioxyalkyl group, an xcfx89,xcfx89-lower alkylene dioxyalkoxy group, a lower cycloalkyl hydroxymethyl group, an aryloxy group, an arylaminosulfonyl group, amino group, a lower alkylamino group, a di lower alkylamino group, a hydroxy lower alkylamino group, a lower acylamino group, a hydroxy lower acylamino group, a lower alkylsulfonylamino group, a pyridyl lower alkoxy group, a lower alkylpyridylalkoxy group, a lower alkoxyhydroxyalkoxy group, a lower thioalkoxyalkoxy group, a lower alkylsulfonylalkoxy group, an N-lower alkylcarbamoyl group, an N,N-di lower alkylcarbamoyl group, an N-hydroxy lower alkylcarbamoyl group, an N-hydroxy lower alkyl-N-lower alkylcarbamoyl group, a halogenated lower alkoxy group, a cyano lower alkoxy group, a hydroxy lower cycloalkoxy group, trifluoromethyl group, trifluoromethoxy group, an amino lower alkoxy group, an N-lower alkyl aminoalkoxy group, an N,N-di lower alkylaminoalkoxy group, a lower acylalkoxy group, a lower acylaminoalkoxy group, a (1,3-dioxolanyl) lower alkyl group, a (1,3-dioxolanyl) lower alkoxy group, an amide lower alkoxy group, a 4-(hydroxyalkyl)tetrahydropyran-4-yl group, 2,3-dihydrobenzofuranyl group, a 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl group, indanonyl group, hydroxyindanyl group, an imidazolyl lower alkoxy group, succinimide group or 2-oxazolidon-3-yl group;
furthermore, R7 represents hydrogen atom, while R8 and R9 may form cyclopentanone ring, hydroxycyclopentane ring, a hydroxyalkylcyclopentane ring, cyclohexanone ring, hydroxycyclohexane ring, a hydroxyalkylcyclohexane ring, 2-hydroxymethyl-2-methylcyclopentanone ring, 1,2-ethylenedioxy ring or methylenedioxy ring;
m or p represents 0 or an integer of 1 to 6;
R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R25, R27 and R29 independently represent hydrogen atom, halogen atom, hydroxy group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group or tetrahydropyranyl group;
the concrete examples of the heteroaryl group include 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 4-thiomorpholinyl group, 4-oxythiomorpholinyl group, 4-dioxythiomorpholinyl group, 1,3-dioxanyl group, 1,4-dioxanyl group, tetrahydrofuranyl group, dihydropyranyl group, 4,4-ethylenedioxypiperidin-1-yl group, 4-hydroxypiperidin-1-ylgroup, 4-methoxypiperidin-1-yl group, 4-acetylpiperazin-1-yl group, a 4-hydroxy lower alkyl piperidin-1-yl group and the like;
the concrete examples of the heteroaryl lower alkyl group include 4-morpholinylmethyl group, 4-thiomorpholinylmethyl group, a (tetrahydropyran-4-yl) lower alkyl group, pyridylmethyl group and the like;
R11 represents hydrogen atom, halogen atom, hydroxy group, a lower alkyl group or a lower alkoxy group;
R24 represents hydrogen atom or a lower alkyl group;
R26 represents hydrogen atom or a hydroxy lower alkyl group;
R28 represents hydrogen atom or a lower alkyl group;
R30 represents hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group or a hydroxy lower alkoxy group;
W represents sulfur atom or oxygen atom;
the bond represented by the following formula:
- - - - -
xe2x80x83represents a single or double bond; and
the bond represented by the following formula: 
xe2x80x83represents trans or cis bond.).
More specifically, the condensed pyridine compound of the present invention preferably include the condensed pyridine compounds represented by the following formulae: 
wherein, R31 has the same meaning as that of the above R1, R32 has the same meaning as that of the above R2 and R33 has the same meaning as that of the above B, respectively.
More specifically, the condensed pyridine compound of the present invention preferably includes the following ones:
(1) 3-(4-benzyloxybutyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(2) 1-(1-methylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(3) 1-(1-methylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(4) 1-(4-ethylpiperazin-1-yl)-3-(4-trifluoromethylphenyl)isoquinoline,
(5) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-fluoropropyl)phenyl]isoquinoline,
(6) 1-(4-ethylpiperazin-1-yl)-3-(2-hydroxyphenyl)isoquinoline,
(7) 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline,
(8) 1-(4-ethylpiperazin-1-yl)-3-(2-methoxyphenyl)isoquinoline,
(9) 1-(4-ethylpiperazin-1-yl)-3-(3-methoxyphenyl)isoquinoline,
(10) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxyphenyl)isoquinoline,
(11) 3-(2,3-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(12) 3-(2,4-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(13) 3-(2,5-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(14) 3-(3,4-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(15) 3-(3,5-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(16) 1-(4-ethylpiperazin-1-yl)-3-(2,4,5-trimethoxyphenyl)isoquinoline,
(17) 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxymethylphenyl)isoquinoline,
(18) 3-[2-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(19) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxypropyl)phenyl]isoquinoline,
(20) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)phenyl]isoquinoline,
(21) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxybutyl)phenyl]isoquinoline,
(22) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxybutyl)phenyl]isoquinoline,
(23) 3-[4-(4-hydroxybutyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(24) 3-[4-(1,3-dihydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(25) 3-[4-(1,3-dihydroxy-3-methylbutyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(26) 3-[4-(3-hydroxy-1-methoxybutyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(27) 1-(1-ethylpiperazin-4-yl)-3-[4-(3-hydroxy-1-fluoropropyl)phenyl]isoquinoline,
(28) 1-(4-ethylpiperazin-1-yl)-3-[4-(4-hydroxymethyl-3-fluoro)phenyl]isoquinoline,
(29) 1-(4-ethylpiperazin-1-yl)-3-[3-fluoro-4-(1-hydroxypropyl)phenyl]isoquinoline,
(30) 3-[3-chloro-4-(3-hydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(31) 3-[3-carboxamide-4-(3-hydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(32) 3-[3-cyano-4-(3-hydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(33) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)-3-methoxyphenyl]isoquinoline,
(34) 3-[3-(3-hydroxypropyl)-4-methoxyphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(35) 3-[3-(4-hydroxybutyl)-4-methoxyphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(36) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(37) 3-[3,4-(2-dihydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(38) 3-[3,5-(2-dihydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(39) 3-[3-chloro-4-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(40) 3-[3-methyl-4-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(41) 3-[3-isopropyl-4-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(42) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxyethoxy)phenyl]isoquinoline,
(43) 3-[3,4-(2-dimethoxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(44) 3-[4-(2-hydroxyethoxy)methylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(45) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-fluoroethoxy)phenyl]isoquinoline,
(46) 3-(3,4-methylenedioxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(47) 1-(1-ethylpiperazin-4-yl)-3-(4-acetonyloxyphenyl)isoquinoline,
(48) 3-[4-(3-aminopropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(49) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-dimethylaminoethoxy)phenyl]isoquinoline,
(50) 3-[4-(3-acetamidepropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(51) 3-(4-cyanomethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(52) 3-[4-(2-cyanoethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(53) 3-[4-(3-cyanopropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(54) 3-[4-(3-methylthiopropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(55) 3-[4-(3-methylsulfonpropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(56) 3-{4-[2-(1-imidazonyl)ethoxy]phenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(57) 3-{4-[3-(4-pyridyl)propoxy]phenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(58) 3-{4-[2-(2-methylpyridin-5-yl)ethoxy]phenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(59) 1-(1-ethylpiperazin-4-yl)-3-[4-(N-ethylcarbamyl)phenyl]isoquinoline,
(60) (Z)-1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyiminomethylphenyl)isoquinoline,
(61) (E)-1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyiminomethylphenyl)isoquinoline,
(62) 3-(4-cyanophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(63) 1-(4-ethylpiperazin-1-yl)-3-(4-N-propylaminocarbonylphenyl)isoquinoline,
(64) 3-[4-(4-hydroxy-1-cyclohexen-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(65) 3-(4-aminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(66) 3-[4-(N,N-dimethylamino)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(67) 3-[4-(2-hydroxyethyl)aminophenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(68) 3-(4-acetamidephenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(69) 3-(4-ethylcarbonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(70) 3-(4-propylcarbonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(71) 3-(4-ethylsulfonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(72) 3-(4-propylsulfonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(73) 3-(4-butylsulfonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(74) 3-(4-sulfonamidephenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(75) 3-[(4-morpholinyl)sulfonylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(76) 3-[(4-thiomorpholinyl)sulfonylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(77) 3-[(1,1-dioxythiomorpholinyl)sulfonylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(78) 3-(4-ethylsulfonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(79) 3-(4-ethylsulfonylaminoethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(80) 3-(4-ethylaminosulfonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(81) 3-(4-propylaminosulfonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(82) 3-[4-(N,N-diethylamino)sulfonylmethylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(83) 3-[4-(tetrahydropyran-4-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(84) 3-[4-(5,6-dihydro-2H-pyran-4-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(85) 3-(4-ethylcarbonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(86) 3-(4-propylcarbonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(87) 3-(4-ethylaminocarbonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(88) 3-(4-propylaminocarbonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(89) 3-(4-butylaminocarbonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(90) 3-(4-methylsulfonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(91) 3-(3-chloro-4-ethylsulfonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(92) 3-(3-chloro-4-propylsulfonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(93) 3-(4-morpholinylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(94) 3-(4-thiomorpholinylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(95) 3-[4-(3-oxazolidinone)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(96) 3-[4-(4,4-ethylenedioxypiperidin-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(97) 1-(4-ethylpiperazin-1-yl)-3-[4-(4-hydroxypiperidin-1-yl)phenyl]isoquinoline,
(98) 1-(4-ethylpiperazin-1-yl)-3-[4-(4-methoxypiperidin-1-yl)phenyl]isoquinoline,
(99) 3-[2-(4-acetylpiperazin-1-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(100) 3-[4-(4-acetylpiperazin-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(101) 3-(2-methoxybenzyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(102) 3-[xcex1-methyl-(4-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(103) 3-[xcex1-hydroxy-(2-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(104) 3-[xcex1-hydroxy-(4-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(105) 3-[xcex1-methyl-xcex1-hydroxy-(4-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(106) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyphenethyl)isoquinoline,
(107) 1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethoxy)phenethyl]isoquinoline,
(108) 1-(1-ethylpiperazin-4-yl)-3-[3-(2-hydroxyethoxy)phenethyl]isoquinoline,
(109) 1-(1-ethylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenethyl]isoquinoline,
(110) 1-(1-ethylpiperazin-4-yl)-3-{3-[2-(2-hydroxyethoxy)phenyl]propyl}isoquinoline,
(111) 3-(2-methoxyphenylcarbonyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(112) 3-(4-methoxyphenylcarbonyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(113) 3-(4-methoxyindan-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(114) 3-(6-methoxyindan-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(115) 3-[4-(2-hydroxyethoxy)indan-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(116) 3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(117) 3-(7-methoxy-1,2-dihydronaphthalen-4-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(118) 3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(119) 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(120) 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(121) 3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(122) 3-(3-hydroxymethylchroman-6-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(123) 1-(4-ethylpiperazin-1-yl)-3-(2-pyridyl)isoquinoline,
(124) 1-(1-ethylpiperazin-4-yl)-3-[5-(2-hydroxyethoxy)pyridin-2-yl]isoquinoline,
(125) 1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethoxy)pyridin-5-yl]isoquinoline,
(126) 1-(1-ethylpiperazin-4-yl)-3-[2-(2-methoxyethoxy)pyridin-5-yl]isoquinoline,
(127) 1-(1-ethylpiperazin-4-yl)-3-[5-(2-methoxyethoxy)pyridin-2-yl]isoquinoline,
(128) 3-(2-propylcarbonylaminopyridin-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(129) 3-[(2-methylsulfonylpyridin)-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(130) 3-[(2-ethylsulfonylpyridin)-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(131) 1-(1-ethylpiperazin-4-yl)-3-(2-butylpyridin-5-yl)isoquinoline,
(132) 1-(1-ethylpiperazin-4-yl)-3-[5-(3-fluoropropyl)pyridin-2-yl)isoquinoline,
(133) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-fluoropropyl)pyridin-5-yl]isoquinoline,
(134) 1-(1-ethylpiperazin-4-yl)-3-[5-(3-hydroxypropyl)pyridin-2-yl]isoquinoline,
(135) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxypropyl)pyridin-5-yl]isoquinoline,
(136) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxybutyl)pyridin-5-yl]isoquinoline,
(137) 1-(1-ethylpiperazin-4-yl)-3-(2-(4-hydroxybutyl)pyridin-5-yl]isoquinoline,
(138) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxy-3-methylbutyl)pyridin-5-yl]isoquinoline,
(139) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-methoxypropyl)pyridin-5-yl]isoquinoline,
(140) 1-(1-ethylpiperazin-4-yl)-3-[3-(3-methoxypropyl)pyridin-5-yl]isoquinoline,
(141) 1-(1-ethylpiperazin-4-yl)-3-[5-(3-methoxypropyl)pyridin-2-yl]isoquinoline,
(142) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-ethoxypropyl)pyridin-5-yl]isoquinoline,
(143) 1-(1-ethylpiperazin-4-yl)-3-[2-[3-(2-propoxy)propyl]pyridin-5-yl]isoquinoline,
(144) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-methoxybutyl)pyridin-5-yl]isoquinoline,
(145) 1-(1-ethylpiperazin-4-yl)-3-{2-[2-(2-hydroxy-2-cyclohexyl)ethynyl]pyridin-4-yl}isoquinoline,
(146) 1-(1-ethylpiperazin-4-yl)-3-[2-(1-butyn-1-yl)pyridin-5-yl]isoquinoline,
(147) 1-(4-ethylpiperazin-1-yl)-3-[2-(morpholin-4-yl)pyridin-5-yl]isoquinoline,
(148) 1-(4-ethylpiperazin-1-yl)-3-[5-(morpholin-4-yl)pyridin-2-yl]isoquinoline,
(149) 3-[2-(2,6-dimethylmorpholin-4-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(150) 1-(4-ethylpiperazin-1-yl)-3-[2-(thiomorpholin-4-yl)pyridin-5-yl]isoquinoline,
(151) 1-(4-ethylpiperazin-1-yl)-3-[2-(S-oxythiomorpholin-4-yl)pyridin-5-yl]isoquinoline,
(152) 1-(4-ethylpiperazin-1-yl)-3-[2-(4-hydroxypiperidin-1-yl)pyridin-5-yl]isoquinoline,
(153) 1-(4-ethylpiperazin-1-yl)-3-[2-(4-methoxypiperidin-1-yl)pyridin-5-yl]isoquinoline,
(154) 1-(4-ethylpiperazin-1-yl)-3-[2-(4-hydroxymethylpiperidin-1-yl)pyridin-5-yl]isoquinoline,
(155) 3-[2-(5,6-dihydro-2H-pyran-4-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(156) 3-(2-(tetrahydropyran-4-yl)pyridin-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(157) 3-[4-[3-(3-pyridyl)propoxy]phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(158) 1-(1-ethylpiperazin-4-yl)-3-(1-phenylpiperazin-4-yl)isoquinoline,
(159) 1-(1-ethylpiperazin-4-yl)-3-[1-(2-pyridyl)piperazin-4-yl]isoquinoline,
(160) 3-[4-(4-morpholinyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(161) 1-(1-ethylpiperazin-4-yl)-3-(2-hydroxymethylthiophen-4-yl)isoquinoline,
(162) 1-(1-ethylpiperazin-4-yl)-3-(2-hydroxymethylthiophen-5-yl)isoquinoline,
(163) 1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethyl)thiophen-5-yl]isoquinoline,
(164) 1-(1-ethylpiperazin-4-yl)-3-[2-(1-hydroxypropyl)thiophen-4-yl]isoquinoline,
(165) 1-(1-ethylpiperazin-4-yl)-3-[2-(1-hydroxypropyl)thiophen-5-yl)isoquinoline,
(166) 3-[2-(tetrahydropyran-4-yl)thiophen-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(167) 1-(1-ethylpiperazin-4-yl)-3-[4-methyl-5-(2-hydroxyethyl)thiazol-2-yl]isoquinoline,
(168) 1-(1-ethylpiperazin-4-yl)-3-(2-hydroxymethylthiazol-5-yl)isoquinoline,
(169) 1-(1-ethylpiperazin-4-yl)-3-[1-(2-hydroxyethyl)pyrazol-3-yl]isoquinoline,
(170) 1-(1-ethylpiperazin-4-yl)-3-[(1-hydroxypropyl)thiazol-5-yl]isoquinoline,
(171) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxypropyl)thiazol-5-yl]isoquinoline,
(172) 1-(1-ethylpiperazin-4-yl)-3-[2-(3-methoxypropyl)thiazol-5-yl]isoquinoline,
(173) 1-(1-ethylpiperazin-4-yl)-3-[2-(4-morpholinyl)thiazol-5-yl]isoquinoline,
(174) 3-(2-propylcarbonylaminopyrimidin-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(175) 3-[2-(5,6-dihydro-2H-pyran-4-yl)thiophen-4-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(176) 3-[2-(5,6-dihydro-2H-pyran-4-yl)thiophen-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(177) 1-(1-ethylpiperazin-4-yl)-3-(phenylethynyl)isoquinoline,
(178) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyphenyl)ethynylisoquinoline,
(179) 1-(1-ethylpiperazin-4-yl)-3-(2-pyridyl)ethynylisoquinoline,
(180) 3-[3-(4-morpholinyl)-1-propynyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(181) 1-(1-ethylpiperazin-4-yl)-3-(3-phenyl-1-propynyl)isoquinoline,
(182) 1-(1-ethylpiperazin-4-yl)-3-(4-phenyl-1-butynyl)isoquinoline,
(183) 1-(1-ethylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenylethynyl]isoquinoline,
(184) 1-(1-ethylpiperazin-4-yl)-3-benzoylethynylisoquinoline,
(185) 1-(1-ethylpiperazin-4-yl)-3-(2,4-dimethoxyphenylethynyl)isoquinoline,
(186) 1-(1-ethylpiperazin-4-yl)-3-[3-(3-methoxypropyl)-5-pyridyl]ethynylisoquinoline,
(187) 1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethoxy)phenyl]ethynylisoquinoline,
(188) 1-(1-ethylpiperazin-4-yl)-3-[3-(2-hydroxyethoxy)-2-pyridyl]ethynylisoquinoline,
(189) 1-(1-ethylpiperazin-4-yl)-3-(trans-2-phenylethenyl)isoquinoline,
(190) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(4-methoxyphenyl)ethenyl]isoquinoline,
(191) 1-(1-ethylpiperazin-4-yl)-3-[cis-2-(4-methoxyphenyl)ethenyl]isoquinoline,
(192) 1-(1-ethylpiperazin-4-yl)-3-(cis-1-methyl-2-phenylethenyl)isoquinoline,
(193) 1-(1-ethylpiperazin-4-yl)-3-(trans-1-methyl-2-phenylethenyl)isoquinoline,
(194) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-hydroxyethoxyphenyl)ethenyl]isoquinoline,
(195) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-mnethoxyphenyl)ethenyl]isoquinoline,
(196) 1-(1-ethylpiperazin-4-yl)-3-(trans-2-methyl-2-phenylethen-1-yl)isoquinoline,
(197) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-fluorophenyl)ethenyl]isoquinoline,
(198) 1-(1-ethylpiperazin-4-yl)-3-[(E)-4-(2-hydroxyethoxy)styryl]isoquinoline,
(199) 1-(1-ethylpiperazin-4-yl)-3-{trans-2-[3-(2-hydroxyethoxy)phenyl]ethenyl}isoquinoline,
(200) 3-{(E)-2-[2-(4-morpholinyl)pyridin-5-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(201) 3-[(E)-2-(4-methylsulfonylphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(202) 3-[(E)-2-(2-methylsulfonylphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(203) 3-[(E)-2-(4-methylsulfonylmethylphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(204) 3-{(E)-2-[3-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(205) 3-{(E)-2-[(4-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(206) 3-{(E)-2-methyl-2-[4-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(207) 3-{(E)-2-methyl-2-[3-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(208) 3-[(E)-2-methoxymethyl-2-phenylethenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(209) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-pyridyl)ethenyl]isoquinoline,
(210) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(4-pyridyl)ethenyl]isoquinoline,
(211) 1-(1-ethylpiperazin-4-yl)-3-[3-(2-methoxy)phenyl-2-propenyl]isoquinoline,
(212) 1-(1-ethylpiperazin-4-yl)-3-[3-(2-hydroxyethoxy)phenyl-1-propenyl]isoquinoline,
(213) 3-{(E)-2-[2-(4-morpholinyl)pyridin-5-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(214) 3-{(E)-2-[3-(4-morpholinyl)pyridazin-6-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(215) 3-{(E)-2-[4-(4-morpholinyl)pyrimidin-6-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(216) 3-{(E)-2-[2-(4-morpholinyl)pyrazin-6-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(217) 3-[1-(4-methoxyphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(218) 1-(1-ethylpiperazin-4-yl)-N-phenyl-3-isoquinolinecarboxamide,
(219) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyanilinomethyl)isoquinoline,
(220) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxybenzylamino)isoquinoline,
(221) 1-(1-ethylpiperazin-4-yl)-4-methoxy-3-(4-methoxyphenyl)isoquinoline,
(222) 1-(1-ethylpiperazin-4-yl)-5-methyl-3-(4-methoxyphenyl)isoquinoline,
(223) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]-6-fluoroisoquinoline,
(224) 1-(1-ethylpiperazin-4-yl)-6-fluoro-3-(4-methoxyphenyl)isoquinoline,
(225) 1-(1-ethylpiperazin-4-yl)-6-methyl-3-(4-methoxyphenyl)isoquinoline,
(226) 1-(4-ethylpiperazin-1-yl)-6-methoxy-3-(4-trifluoromethylphenyl)isoquinoline,
(227) 1-(4-ethylpiperazin-1-yl)-6-methoxy-3-(4-methoxyphenyl)isoquinoline,
(228) 1-(1-ethylpiperazin-4-yl)-7-methyl-3-(4-methoxyphenyl)isoquinoline,
(229) 1-(4-ethylpiperazin-1-yl)-7-fluoro-3-(4-methoxyphenyl)isoquinoline,
(230) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]-7-fluoroisoquinoline,
(231) 1-(4-ethylpiperazin-1-yl)-7-methoxy-3-phenylisoquinoline,
(232) 1-(4-ethylpiperazin-1-yl)-7-methoxy-3-(2-methoxyphenyl)isoquinoline,
(233) 1-(1-ethylpiperazin-4-yl)-8-fluoro-3-(4-methoxyphenyl)isoquinoline,
(234) 1-(1-ethylpiperazin-4-yl)-8-fluoro-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(235) 1-(1-ethylpiperazin-4-yl)-8-methoxy-3-(4-methoxyphenyl)isoquinoline,
(236) 1-(1-propylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(237) 1-(1-propylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(238) 1-(1-isopropylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(239) 1-(1-cyclopropylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(240) 1-(1-allylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(241) 1-[1-(2-fluoroethyl)piperazin-4-yl]-3-(4-methoxyphenyl)isoquinoline,
(242) 1-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(4-methoxyphenyl)isoquinoline,
(243) 3-(4-ethylsulfonylaminomethylphenyl)-1-[4-(2-hydroxyethyl)piperazin-1-yl]isoquinoline,
(244) 8-(4-ethylpiperazin-1-yl)-6-(4-methoxyphenyl)pyrido[2,3-c]pyridine,
(245) 8-(1-ethylpiperazin-4-yl)-6-[4-(2-hydroxyethoxy)phenyl]-1,7-naphthyridine,
(246) 8-(1-ethylpiperazin-4-yl)-6-{4-[(S)-2-hydroxypropoxy]phenyl}-1,7-naphthyridine,
(247) 8-(1-ethylpiperazin-4-yl)-6-[4-(3-hydroxypropyl)phenyl]-1,7-naphthyridine,
(248) 8-(1-ethylpiperazin-4-yl)-6-[4-(3-hydroxybutyl)phenyl]-1,7-naphthyridine,
(249) 8-(1-ethylpiperazin-4-yl)-6-[4-(3-hydroxy-1-fluoropropyl)phenyl]-1,7-naphthyridine,
(250) 8-(1-ethylpiperazin-4-yl)-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]-1,7-naphthyridine,
(251) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyphenyl)-2,6-naphthyridine,
(252) 5-(1-ethylpiperazin-4-yl)-7-(4-methoxyphenyl)-1,6-naphthyridine,
(253) 5-[4-(2-hydroxyethoxy)phenyl]-7-(4-methylpiperazin-1-yl)thieno[2,3-c]pyridine,
(254) 7-(1-ethylpiperazin-4-yl)-5-[4-(1-hydroxypentyl)phenyl]thieno[2,3-c]pyridine,
(255) 7-(1-ethylpiperazin-4-yl)-5-[4-(1-hydroxy-3-methylbutyl)phenyl]thieno[2,3-c]pyridine,
(256) 7-(1-ethylpiperazin-4-yl)-5-[4-(3-hydroxy-1-fluoropropyl)phenyl]thieno[2,3-c]pyridine,
(257) 5-[4-(3-hydroxypropyl)-3-chlorophenyl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(258) 7-(1-ethylpiperazin-4-yl)-5-[3-(2-hydroxyethoxy)phenyl]thieno[2,3-c]pyridine,
(259) 7-(4-ethylpiperazin-1-yl)-5-(4-hydroxyethoxyphenyl)thieno[2,3-c]pyridine,
(260) 7-(1-ethylpiperazin-4-yl)-5-[4-(2-hydroxy-2-methylpropoxy)phenyl]thieno[2,3-c]pyridine,
(261) 5-[3-(3-hydroxypropyl)-4-methoxyphenyl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(262) 5-[4-(3-hydroxypropyl)-3-cyanophenyl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(263) 5-[2-(4-morpholinyl)pyridin-5-yl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(264) 5-[2-(4-thiomorpholinyl)pyridin-5-yl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(265) 5-[2-(4-hydroxypiperidin-1-yl)pyridin-5-yl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(266) 5-[4-(5,6-dihydro-2H-pyran-4-yl)phenyl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(267) 5-[2-(2-methoxyethoxy-2-methyl)pyridin-5-yl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(268) 5-[2-(2-hydroxyethoxy)pyridin-5-yl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(269)5-[2-(2-methoxyethoxy)pyridin-5-yl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(270) 5-[4-(4-hydroxycyclohexen-1-yl)phenyl]-7-(4-ethylpiperazin-1-yl)thieno[2,3-c]pyridine,
(271) 7-(1-ethylpiperazin-4-yl)-5-(4-pentanoylphenyl)thieno[2,3-c]pyridine,
(272) 7-(1-ethylpiperazin-4-yl)-5-[4-(3-methylbutanoyl)phenyl]thieno[2,3-c]pyridine,
(273) 7-(1-ethylpiperazin-4-yl)-5-[4-(N-cyclohexylamide)phenyl]thieno[2,3-c]pyridinecarboxamide,
(274) 7-(1-ethylpiperazin-4-yl)-5-[4-(pyrrolidinyl-1-carbonyl)phenyl]thieno[2,3-c]pyridine,
(275) 5-[4-(2-hydroxyethoxy)phenyl]-7-[4-(2-hydroxyethyl)piperazin-1-yl]thieno[3,2-c]pyridine,
(276) 5-(4-methoxyphenyl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]thieno[2,3-c]pyridine,
(277) 4-(4-ethylpiperazin-1-yl)-6-(4-methoxyphenyl)thieno[3,4-c]pyridine,
(278) 4-(4-ethylpiperazin-1-yl)-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,4-c]pyridine,
(279) 4-(4-methylpiperazin-1-yl)-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(280) 4-(4-ethylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine,
(281) 4-(4-ethylpiperazin-1-yl)-6-[4-(1-hydroxyethyl)phenyl]thieno[3,2-c]pyridine,
(282) 4-(4-ethylpiperazin-1-yl)-6-[4-(1-hydroxypropyl)phenyl]thieno[3,2-c]pyridine,
(283) 4-(4-ethylpiperazin-1-yl)-6-[4-(1-hydroxybutyl)phenyl]thieno[3,2-c]pyridine,
(284) 4-(1-ethylpiperazin-4-yl)-6-[3-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(285) 4-(1-ethylpiperazin-4-yl)-6-[4-(3-hydroxybutyl)phenyl]thieno[3,2-c]pyridine,
(286) (4-ethylpiperazin-1-yl)-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(287) 4-(4-ethylpiperazin-1-yl)-6-[4-(2-hydroxypropoxy)phenyl]thieno[3,2-c]pyridine,
(288) 6-[4-(2-methyl-2-hydroxypropoxy)phenyl]-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine,
(289) 6-[4-(2-methyl-2-hydroxypropoxy)phenyl]-4-(4-propylpiperazin-1-yl)thieno[3,2-c]pyridine,
(290) 6-[4-(2-methyl-2-hydroxypropoxy)phenyl]-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine,
(291) 4-(4-ethylpiperazin-1-yl)-6-[4-(3-hydroxy-3-methylbutyl)phenyl]thieno[3,2-c]pyridine,
(292) 6-[4-(4-methyl-4-hydroxypentyloxy)phenyl]-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine,
(293) 4-(4-propylpiperazin-1-yl)-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(294) 6-[4-(2-methyl-2-hydroxypropoxy)phenyl]-4-[4-(2-fluoroethyl)piperazin-1-yl)thieno[3,2-c]pyridine,
(295) 4-[4-(2-fluoroethyl)piperazin-1-yl]-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(296) 6-[4-(2-methyl-2-hydroxypropoxy)phenyl]-4-[4-(2-hydroxyethyl)piperazin-1-yl]thieno[3,2-c]pyridine,
(297) 6-[4-(2-methyl-2-hydroxypropoxy)phenyl]-4-[4-(2-phenylethyl)piperazin-1-yl]thieno[3,2-c]pyridine,
(298) 7-(1-ethylpiperazin-4-yl)-5-[3-(2-hydroxyethoxy)phenyl]furo[2,3-c]pyridine,
(299) 7-(1-ethylpiperazin-4-yl)-5-[4-(3-hydroxypropyl)phenyl]furo[2,3-c]pyridine,
(300) 7-(1-ethylpiperazin-4-yl)-5-[4-(3-hydroxybutyl)phenyl]furo[2,3-c]pyridine,
(301) 7-(1-ethylpiperazin-4-yl)-5-[4-(2-hydroxyethoxy)phenyl]furo[2,3-c]pyridine,
(302) 7-(1-ethylpiperazin-4-yl)-5-{4-[(R)-2-hydroxy-1-methylethoxy]phenyl}furo[2,3-c]pyridine,
(303) 7-(1-ethylpiperazin-4-yl)-5-{4-[(S)-2-hydroxy-1-methylethoxy]phenyl}furo[2,3-c]pyridine,
(304) 7-(1-ethylpiperazin-4-yl)-5-{4-[(S)-2-hydroxypropoxy]phenyl}furo[2,3-c]pyridine,
(305) 7-(1-ethylpiperazin-4-yl)-5-{4-[(R)-2-hydroxypropoxy]phenyl}furo[2,3-c]pyridine,
(306) 7-(1-ethylpiperazin-4-yl)-5-[4-(3-hydroxy-3-methylbutoxy)phenyl]furo[2,3-c]pyridine,
(307) 7-(1-ethylpiperazin-4-yl)-5-{trans-2-[4-(2-hydroxyethoxy)phenyl]ethenyl}furo[2,3-c]pyridine,
(308) 7-(1-ethylpiperazin-4-yl)-5-{trans-2-[2-(2-hydroxyethoxy)phenyl]ethenyl}furo[2,3-c]pyridine,
(309) 1-(1-ethylpiperazin-4-yl)-3-[4-(2-hydroxy-2-methylpropoxy)phenyl]isoquinoline,
(310) 1-(1-ethylpiperazin-4-yl)-3-(3-phenyl-3-hydroxy-1-propynyl)isoquinoline,
(311) 1-(1-ethylpiperazin-4-yl)-8-methyl-3-(4-methoxyphenyl)isoquinoline,
(312) 1-(1-ethylpiperazin-4-yl)-4-methyl-3-(4-methoxyphenyl)isoquinoline,
(313) 1-[1-(2-cyanoethyl)piperazin-4-yl]-3-(4-methoxyphenyl)isoquinoline,
(314) 1-[1-(carbamoylmethyl)piperazin-4-yl]-3-(4-methoxyphenyl)isoquinoline,
(315) 1-(4-ethylsulfonylpiperazin-1-yl)-3-(4-methoxyphenyl)isoquinoline,
(316) 4-piperidinyl-6-[4-(2-methyl-2-hydroxypropoxy)phenyl]thieno[3,2-c]pyridine,
(317) 7-(1-ethylpiperazin-4-yl)-5-[4-(3-hydroxypropoxy)phenyl]furo[2,3-c]pyridine,
(318) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxyphenyl)isoquinoline,
(319) 1-{N-[2-(2-dimethylamino)ethyl]-N-methylamino}-3-(4-methoxyphenyl)isoquinoline,
(320) 1-(4-morpholinyl)-3-(4-methoxyphenyl)isoquinoline,
(321) 1-(1-ethyl-2-pyrrolidinyl)methylamino-3-(4-methoxyphenyl)isoquinoline,
(322) 3-(4-methoxyphenyl)-1-[2-(2-pyridyl)ethyl]aminoisoquinoline,
(323) 1-[2-(4-morpholinyl)ethyl]amino-3-(4-methoxyphenyl)isoquinoline,
(324) 1-(1-imidazolyl)-3-(4-methoxyphenyl)isoquinoline,
(325) 1-[4-(piperidin-1-yl)piperidin-1-yl]-3-(4-methoxyphenyl)isoquinoline,
(326) 1-(1,4,5,6-tetrahydropyrimidin-1-yl)-3-(4-methoxyphenyl)isoquinoline,
(327) 1-(1-ethylhomopiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(328) 3-(4-methoxyphenyl)-1-(4-ethylpiperazin-1-yl)methylisoquinoline,
(329) 1-(4-ethylpiperazin-1-yl)-3-[3-(2-hydroxyethoxy)phenyl]isoquinoline,
(330) 1-(4-ethylpiperazin-1-yl)-3-(4-ethoxyphenyl)isoquinoline,
(331) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropoxy)phenyl]isoquinoline,
(332) 1-(4-ethylpiperazin-1-yl)-3-(3,4-ethylenedioxyphenyl)isoquinoline,
(333) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-methoxypropyl)phenyl]isoquinoline,
(334) 1-(4-ethylpiperazin-1-yl)-3-[4-(n-butyl)phenyl]isoquinoline,
(335) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxypyridin-2-yl)isoquinoline,
(336) 1-(4-ethylpiperazin-1-yl)-3-[4-(1,3-dioxolan-2-ylmethyloxy)phenyl]isoquinoline,
(337) 1-(4-ethylpiperazin-1-yl)-3-[4-(2,3-dihydroxypropoxy)phenyl]isoquinoline,
(338) 1-(4-ethylpiperazin-1-yl)-3-(4-carbamoylmethoxyphenyl)isoquinoline,
(339) 1-(4-ethylpiperazin-1-yl)-3-(4-trifluoromethoxyphenyl)isoquinoline,
(340) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)-3-methoxyphenyl]isoquinoline,
(341) 1-(4-ethylpiperazin-1-yl)-3-(4-methylthiophenyl)isoquinoline,
(342) 1-(4-ethylpiperazin-1-yl)-3-(4-methylsulfonylphenyl)isoquinoline,
(343) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxy-3-methoxypropoxy)phenyl]isoquinoline,
(344) 1-(4-ethylpiperazin-1-yl)-3-(2-methoxypyridin-5-yl)isoquinoline,
(345) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxy-1-methylethyl)phenyl]isoquinoline,
(346) 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-hydroxyethyl)carbamoyl]phenyl}isoquinoline,
(347) 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-hydroxyethyl)sulfamoyl]phenyl}isoquinoline,
(348) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxyethyl)phenyl)isoquinoline,
(349) 1-(4-ethylpiperazin-1-yl)-3-[4-(propylsulfonyl)phenyl]isoquinoline,
(350) 1-(4-ethylpiperazin-1-yl)-3-{4-[(3-methoxypropyl)sulfonyl]phenyl}isoquinoline,
(351) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethyl)phenyl]isoquinoline,
(352) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)sulfonylphenyl]isoquinoline,
(353) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-propylsulfamoyl)phenyl]isoquinoline,
(354) 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-methoxyethyl)sulfamoyl]phenyl}isoquinoline,
(355) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-fluoropropyl)sulfonylphenyl]isoquinoline,
(356) 1-(4-ethylpiperazin-1-yl)-3-[4-(pyrrolidin-1-yl)sulfonylphenyl]isoquinoline,
(357) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-ethylsulfamoyl)phenyl]isoquinoline,
(358) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-methyl-N-propylsulfamoyl)phenyl]isoquinoline,
(359) 1-(4-ethylpiperazin-1-yl)-3-[4-(N,N-diethylsulfamoyl)phenyl]isoquinoline,
(360) 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(1-methylpropyl)sulfamoyl]phenyl}isoquinoline,
(361) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-methylsulfamoyl)phenyl]isoquinoline,
(362) 1-(4-ethylpiperazin-1-yl)-3-[4-(N,N-dimethylsulfamoyl)phenyl]isoquinoline,
(363) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-cyclopropylsulfamoyl)phenyl]isoquinoline,
(364) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-ethylcarbamoyl)phenyl]isoquinoline,
(365) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-methylcarbamoyl)phenyl]isoquinoline,
(366) 1-(4-ethylpiperazin-1-yl)-3-[4-(ethylsulfonyl)phenyl]isoquinoline,
(367) 1-(4-ethylpiperazin-1-yl)-3-(3-fluoro-4-methoxyethoxyphenyl)isoquinoline,
(368) 1-(4-ethylpiperazin-1-yl)-3-(3,5-difluoro-4-methoxyethoxyphenyl)isoquinoline,
(369) 1-(4-ethylpiperazin-1-yl)-3-[3-fluoro-4-(2-hydroxyethoxy)phenyl]isoquinoline,
(370) 1-(4-ethylpiperazin-1-yl)-3-[3,5-difluoro-4-(2-hydroxyethoxy)phenyl]isoquinoline,
(371) 1-(4-ethylpiperazin-1-yl)-3-[3,5-difluoro-4-(2-fluoroethoxy)phenyl]isoquinoline,
(372) 1-[4-(2-hydroxyethyl)piperazin-1-yl]-3-[4-(N-ethylsulfamoyl)phenyl]isoquinoline,
(373) 1-[4-(2-hydroxyethyl)piperazin-1-yl]-3-[4-(propylsulfonyl)phenyl]isoquinoline,
(374) 1-(4-ethylpiperazin-1-yl)-3-(phenylthio)isoquinoline,
(375) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-oxopropyl)phenyl]isoquinoline,
(376) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxypropyl)phenyl]isoquinoline,
(377) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxy-2-methylpropyl)phenyl]isoquinoline,
(378) 1-(4-ethylpiperazin-1-yl)-3-(2-pyridylthio)isoquinoline,
(379) 1-(4-ethylpiperazin-1-yl)-3-(4-butyrylphenyl)isoquinoline,
(380) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxyiminobutyl)phenyl]isoquinoline,
(381) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-methyl-N-propylcarbamoyl)phenyl]isoquinoline,
(382) 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-hydroxyethyl)-N-methylcarbamoyl]phenyl}isoquinoline,
(383) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxy-1-methylpropyl)phenyl]isoquinoline,
(384) 1-(4-ethylpiperazin-1-yl)-3-[4-(N-propylcarbamoyl)-3-fluorophenyl]isoquinoline,
(385) 1-(4-ethylpiperazin-1-yl)-3-[3-fluoro-4-(2-hydroxyethyl)phenyl]isoquinoline,
(386) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxy-2-methylpropyl)phenyl]isoquinoline,
(387) 1-(4-ethylpiperazin-1-yl)-3-[4-(1,2-dihydroxyethyl)phenyl]isoquinoline,
(388) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxy-3-methylbutyl)phenyl]isoquinoline,
(389) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxy-2,2-dimethylpropyl)phenyl]isoquinoline,
(390) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxy-1,1-dimethylpropyl)phenyl]isoquinoline,
(391) 1-(4-ethylpiperazin-1-yl)-3-[4-(1,3-dihydroxy-2,2-dimethylpropyl)phenyl]isoquinoline,
(392) 1-(4-ethylpiperazin-1-yl)-3-{4-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]phenyl}isoquinoline,
(393) 1-(4-ethylpiperazin-1-yl)-3-(2-hydroxymethylindan-5-yl)isoquinoline,
(394) 1-(4-ethylpiperazin-1-yl)-3-[(3,4-dihydroxymethyl)phenyl]isoquinoline,
(395) 1-(4-ethylpiperazin-1-yl)-3-[4-(1,4-dioxan-2-yl)phenyl]isoquinoline,
(396) 1-(4-ethylpiperazin-1-yl)-3-[4-(tetrahydrofuran-2-yl)phenyl]isoquinoline,
(397) 1-(4-ethylpiperazin-1-yl)-3-[4-(cis-4-hydroxycyclohexyl)phenyl]isoquinoline,
(398) 1-(4-ethylpiperazin-1-yl)-3-[4-(trans-4-hydroxycyclohexyl)phenyl]isoquinoline,
(399) 1-(4-ethylpiperazin-1-yl)-3-[4-(tetrahydropyran-4-yl)methylphenyl]isoquinoline,
(400) 4-chloro-1-(4-ethylpiperazin-1-yl)-3-(4-methoxyphenyl)isoquinoline,
(401) 1-(4-ethylpiperazin-1-yl)-3-[4-(cis-4-hydroxytetrahydropyran-2-yl)phenyl]isoquinoline,
(402) 1-(4-ethylpiperazin-1-yl)-3-[4-(trans-4-hydroxytetrahydropyran-2-yl)phenyl]isoquinoline,
(403) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxypropoxy)phenyl]isoquinoline,
(404) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxy-1-methylethoxy)phenyl]isoquinoline,
(405) 1-(4-ethylpiperazin-1-yl)-3-(2-methoxypyridin-4-yl)isoquinoline,
(406) 1-(4-ethylpiperazin-1-yl)-3-(2-benzyloxypyridin-4-yl)isoquinoline and 1-(4-ethylpiperazin-1-yl)-3-(2-chloropyridin-4-yl)isoquinoline,
(407) 1-(4-ethylpiperazin-1-yl)-3-[2-(2-methoxyethoxy)pyridin-4-yl]isoquinoline,
(408) 1-(4-ethylpiperazin-1-yl)-3-(4-carbamoylphenyl)isoquinoline,
(409) 1-(4-ethylpiperazin-1-yl)-3-[4-(cyclohexylhydroxymethyl)phenyl]isoquinoline,
(410) 1-(4-ethylpiperazin-1-yl)-3-[4-(4-hydroxytetrahydropyran-4-yl)phenyl]isoquinoline,
(411) 1-(4-ethylpiperazin-1-yl)-3-{4-[bis(1,3-thiazol-2-yl)hydroxymethyl]phenyl}isoquinoline,
(412) 1-(4-ethylpiperazin-1-yl)-3-[4-(1,3-thiazol-2-yl)hydroxymethylphenyl]isoquinoline,
(413) 1-(4-ethylpiperazin-1-yl)-3-[(3-pyridyl)hydroxymethyl]isoquinoline,
(414) 1-(4-ethylpiperazin-1-yl)-3-(1-indanon-5-yl)isoquinoline,
(415) 1-(4-ethylpiperazin-1-yl)-3-(1-hydroxyindan-5-yl)isoquinoline,
(416) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxy-3-methylbutyl)-3-fluorophenyl]isoquinoline,
(417) 1-(4-ethylpiperazin-1-yl)-3-[3-cyano-4-(2-hydroxyethoxy)phenyl]isoquinoline,
(418) 1-(4-ethylpiperazin-1-yl)-3-[3-(3-hydroxypropyl)phenyl]isoquinoline,
(419) 1-(4-ethylpiperazin-1-yl)-3-benzylisoquinoline,
(420) 1-(4-ethylpiperazin-1-yl)-3-(2-hydroxy-2-phenylethyl)isoquinoline,
(421) 3-benzamide-1-(4-ethylpiperazin-1-yl)isoquinoline,
(422) 3-benzenesulfoneamide-1-(4-ethylpiperazin-1-yl)isoquinoline,
(423) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxybenzenesulfonamide)isoquinoline,
(424) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxyphenoxymethyl)isoquinoline,
(425) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)-2-methoxyphenyl]isoquinoline,
(426) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxycyclohexyloxy)phenyl]isoquinoline,
(427) 4-(4-ethylpiperazin-1-yl)-2-(4-methoxyphenyl)quinazoline,
(428) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxyphenyl)-7-azaisoquinoline,
(429) 7-(4-ethylpiperazin-1-yl)-5-[2-(3-hydroxypropyl)pyridin-5-yl]thieno[2,3-c]pyridine,
(430) 7-(4-ethylpiperazin-1-yl)-5-[3-(2-hydroxyethoxy)styryl]thieno[2,3-c]pyridine,
(431) 7-(4-ethylpiperazin-1-yl)-5-[4-(2-hydroxyethoxy)styryl]thieno[2,3-c]pyridine,
(432) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxypropyl)phenyl]thieno[2,3-c]pyridine,
(433) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxypropyl)-3-methoxyphenyl)thieno[2,3-c]pyridine,
(434) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxypropoxy)phenyl]thieno[2,3-c]pyridine,
(435) 7-(4-ethylpiperazin-1-yl)-5-[4-(2-hydroxypropoxy)phenyl]thieno[2,3-c]pyridine,
(436) 7-(4-ethylpiperazin-1-yl)-5-[4-(2-hydroxypropyl)phenyl]thieno[2,3-c]pyridine,
(437) 7-(4-ethylpiperazin-1-yl)-5-[3-chloro-4-(2-hydroxyethoxy)phenyl]thieno[2,3-c]pyridine,
(438) 7-(4-ethylpiperazin-1-yl)-5-[4-(1-methyl-2-hydroxyethoxy)phenyl]thieno[2,3-c]pyridine,
(439) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxy-3-methylbutyl)phenyl]thieno[2,3-c]pyridine,
(440) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxybutyl)phenyl]thieno[2,3-c]pyridine,
(441) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxy-2-methylpropyl)phenyl]thieno[2,3-c]pyridine,
(442) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxy-2,2-dimethylpropyl)phenyl]thieno[2,3-c]pyridine,
(443) 7-(4-ethylpiperazin-1-yl)-5-[4-(3-hydroxy-1,1-dimethylpropyl)phenyl]thieno[2,3-c]pyridine,
(444) 7-(4-ethylpiperazin-1-yl)-5-[4-(2-hydroxypropylthio)phenyl]thieno[2,3-c]pyridine,
(445) 7-(4-ethylpiperazin-1-yl)-5-(4-methanesulfonylphenyl)thieno[2,3-c]pyridine,
(446) 7-(4-ethylpiperazin-1-yl)-5-[4-(1-hydroxybutyl)phenyl]thieno[2,3-c]pyridine,
(447) 7-(4-ethylpiperazin-1-yl)-5-[4-(N-methylcarbamoyl)phenyl]thieno[2,3-c]pyridine,
(448) 7-(4-ethylpiperazin-1-yl)-5-[4-(N-ethylcarbamoyl)phenyl]thieno[2,3-c]pyridine,
(449) 7-(4-ethylpiperazin-1-yl)-5-[4-(N-propylcarbamoyl)phenyl]thieno[2,3-c]pyridine,
(450) 7-(4-ethylpiperazin-1-yl)-5-(4-ethanesulfonylphenyl]thieno[2,3-c]pyridine,
(451) 7-(4-ethylpiperazin-1-yl)-5-(4-propanesulfonylphenyl)thieno[2,3-c]pyridine,
(452) 7-(4-ethylpiperazin-1-yl)-5-[4-(N-butylcarbamoyl)phenyl]thieno[2,3-c]pyridine,
(453) 7-(4-ethylpiperazin-1-yl)-5-[4-(N-cyclopentylcarbamoyl)phenyl]thieno[2,3-c]pyridine,
(454) 7-(4-ethylpiperazin-1-yl)-5-[4-(cis-4-hydroxytetrahydropyran-2-yl)phenyl]thieno[2,3-c]pyridine,
(455) 7-(4-ethylpiperazin-1-yl)-5-[4-(trans-4-hydroxytetrahydropyran-2-yl)phenyl]thieno[2,3-c]pyridine,
(456) 7-(4-ethylpiperazin-1-yl)-5-(2,3-dihydro-2-hydroxymethyl-2-methylbenzofuran-5-yl)phenyl]thieno[2,3-c]pyridine,
(457) 7-(4-ethylpiperazin-1-yl)-5-[4-(cyclohexylhydroxymethyl)phenyl]thieno[2,3-c]pyridine,
(458) 7-(4-ethylpiperazin-1-yl)-5-[4-(cyclopentylhydroxymethyl)phenyl]thieno[2,3-c]pyridine,
(459) 7-(4-ethylpiperazin-1-yl)-5-(4-methoxyphenyl)thieno[2,3-c]pyridine,
(460) 4-(4-ethylpiperazin-1-yl)-6-[4-(1,3-dioxolan-2-yl)methoxyphenyl]thieno[3,2-c]pyridine,
(461) 4-(4-ethylpiperazin-1-yl)-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(462) 4-(4-ethylpiperazin-1-yl)-6-[4-(3-hydroxypropoxy)phenyl]thieno[3,2-c]pyridine,
(463) 4-(4-ethylpiperazin-1-yl)-6-[4-(2-hydroxy-1-methylethoxy)phenyl]thieno[3,2-c]pyridine,
(464) 4-(4-ethylpiperazin-1-yl)-6-[4-(3-hydroxy-1-propynyl)phenyl]thieno[3,2-c]pyridine,
(465) 4-(4-ethylpiperazin-1-yl)-6-[4-(3-hydroxypropyl)phenyl]thieno[3,2-c]pyridine,
(466) 4-(4-ethylpiperazin-1-yl)-6-(4-(3-hydroxy-3-methyl-1-butynyl)phenyl]thieno[3,2-c]pyridine,
(467) 7-(4-ethylpiperazin-1-yl)-5-(4-methoxyphenyl)furo[2,3-c]pyridine and
(468) 4-(4-ethylpiperazin-1-yl)-6-(4-methoxyphenyl)furo[3,2-c]pyridine.
Among the condensed pyridine compound according to the present invention, those which are particularly preferable from the viewpoint of pharmacological effects or safety are, for example, the following ones:
(1) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxypropyl)phenyl]isoquinoline,
(2) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)phenyl]isoquinoline,
(3) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxybutyl)phenyl]isoquinoline,
(4) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(5) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxyethoxy)phenyl]isoquinoline,
(6) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-fluoroethoxy)phenyl]isoquinoline,
(7) 3-[4-(2-cyanoethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(8) 7-(4-ethylpiperazin-1-yl)-5-(4-hydroxyethoxyphenyl)thieno[2,3-c]pyridine,
(9) (4-ethylpiperazin-1-yl)-6-[4-(2-hydroxyethoxy)phenyl]thieno[3,2-c]pyridine,
(10) 4-(4-ethylpiperazin-1-yl)-6-[4-(2-hydroxypropoxy)phenyl]thieno[3,2-c]pyridine and
(11) 6-[4-(2-methyl-2-hydroxy)propoxyphenyl]-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine.
Although some of the condensed pyridine compound of the present invention occur as stereomers, either one of these stereomers or a mixture thereof may be used in the present invention without restriction. Similarly, either one of geometrical isomers or a mixture thereof may be employed herein without any restriction. In the case of polymorphic crystals, either one of the crystal forms or a mixture thereof may be used in the present invention without restriction, too. Moreover, use may be made of both anhydrides and hydrates.
The pharmacologically acceptable salts to be used in the present invention may be arbitrary salts of the condensed pyridine compound of the present invention without particular restriction. Examples thereof include inorganic acid addition salts such as hydrochlorides, sulfates, nitrates, hydrobromides, hydriodides, perchlorates and phosphates, organic acid addition salts such as oxalates, maleates, fumarates and succinates, sulfonic acid addition salts such as methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and camphorsulfonates, and amino acid addition salts. Among all, it is preferable to use hydrochlorides and oxalates thereof.
Sequentially, a general process of producing the compound of the present invention will be described below, with no limitation. It can be prepared by other synthetic routes.
The compound can be prepared by reacting isoquinolin-1-one compound (III) with a halogenating agent to give 1-halogenated isoquinoline compound (IV), and reacting the resulting compound which piperazine or 1-substituted piperazine. (See the following formulae. In the formulae, R3, R31, R32, R33 and n have the same meanings as described above. X represents halogen atom.) 
Herein, the isoquinolin-1-one compound (III) includes a great number of known compounds, which are available as industrial raw materials or reagents. And, These compound can be produced by methods described in known references.
The isoquinolin-1-one compound (III) can be halogenated by general methods. Herein, any type of halogenating agents can be used, with no limitation. Generally, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, sulfuryl chloride, oxazolyl chloride, phosphorus oxybromide, phosphorus tribromide and the like are used; among them, phosphorus oxychloride is preferable.
The reaction of the 1-halogenated isoquinoline compound (IV) with piperazine or 1-substituted piperazine can be effected by general methods for N-alkylation.
By chemically modifying the substituent of the 1-piperidylisoquinoline compound (V) thus prepared, furthermore, a novel 1-piperidylisoquinoline compound (V) can be derived.
Also in this case, in the same manner as described above in (1), the compound can be prepared by reacting dihydropyridopyridin-8-one compound (VI) with a halogenating agent to give 8-halogenated pyridopyridine compound (VII), and then reacting the resulting compound with piperazine or 1-substituted piperazine. (See the following formulae. In the formulae, R3, R31, R32, R33 and n have the same meanings as described above. X represents halogen atom.) 
Also in this case, in the same manner as described above in (1) or (2), the compound can be prepared by reacting thienopyridopyridin-7-one compound (VIII) with a halogenating agent to give 7-halogenated thienopyridine compound (IX), and then reacting the resulting compound with piperazine or 1-substituted piperazine. (See the following formulae. In the formulae, R3, R31, R32, R33 and n have the same meanings as described above. X represents halogen atom.) 
Also in this case, in the same manner as described above in any of (1) to (3), the compound can be prepared by reacting furopyridin-7-one compound (X) with a halogenating agent to give 7-halogenated furopyridine compound (XI), and then reacting the resulting compound with piperazine or 1-substituted piperazine. (See the following formulae. In the formulae, R3, R31, R32 R33 and n have the same meanings as described above. X represents halogen atom.) 
Examples of the dosage forms of the compounds of the present invention include oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments, patches and suppositories, and injections. These preparations may be produced by the conventional methods with the use of pharmaceutical carriers commonly employed in the art.
Namely, oral preparations may be produced by blending the 1,4-substituted cyclic amine derivative or a pharmacologically acceptable salt thereof with fillers optionally together with binders, disintegrating agents, lubricating agents, coloring agents, corrigents, etc. and then processing the resultant blends into powders, fine granules, granules, tablets, coated tablets, capsules, etc. by the conventional methods.
As the fillers, use may be made of, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide. As the binders, use may be made of, for example, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymers and meglumine. As the disintegrating agents, use may be made of, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin and calcium carboxymethylcellulose. As the lubricating agents, use may be made of, for example, magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. As the coloring agents, use may be made of those authorized as pharmaceutical additives. As the corrigents, use may be made of, for example, cocoa powder, mentha, aromatic powder, mentha oil, borneol and powdered cinnamon bark. Needless to say, these tablets and granules may be appropriately coated with sugar, etc., if necessary.
Injections are produced by blending the condensed pyridine compound or a pharmacologically acceptable salt thereof with pH regulating agents, resolvents, tonicity agents, etc., optionally together with dissolution aids, stabilizers, etc. and processing the resultant blends into preparations by the conventional methods.
External preparations may be produced by the conventional methods without restriction. As the bases, therefore, use can be made of various materials commonly used in drugs, quasi drugs, cosmetics, etc.
Particular examples of the base materials include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water. If needed, it is possible to further add pH regulating agents, antioxidants, chelating agents, antiseptics, fungicides, coloring agents, perfumes, etc., though the materials usable as the base in the external preparations of the present invention are not restricted thereto. If necessary, it is also possible to furthermore add other ingredients capable of inducing differentiation, blood flow accelerators, bactericides, antiinflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, etc. The above materials may be added in such amounts as to give the concentrations thereof commonly employed in the production of external preparations.
The clinical dose of the condensed pyridine compound of the present invention or a pharmacologically acceptable salt thereof is not restricted but varies depending on the symptoms, severity, age, complications, etc. Also, the dose thereof varies depending on the type of the salt, administration route, etc. In general, these compounds are administered to an adult in a dose of from 0.01 to 1000 mg, preferably from 0.1 to 500 mg and still preferably from 0.5 to 100 mg, per day orally, intravenously, as suppositories or percutaneously.
Next, the results of a binding test on the compounds of the present invention to serotonin 1A and serotonin 2 receptors will be given so as to illustrate the effects of the present invention. Moreover, the results of a binding test on these compounds to an xcex11 adrenalin receptor will be given so as to illustrate the safety thereof.
It is reported in, for example, the following publications that compounds with a serotonin antagonism are usable as medicament for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia:
(1) Saishin Igaku Jiten, 3rd impression of 1st edition, p. 809 xe2x80x9cSEROTONINxe2x80x9d, Iyaku Shuppan
(2) Stedman""s Medical Dictionary, 24th edition, p. 1227 xe2x80x9cserotoninxe2x80x9d, Williams and Wilkins
(3) Shinkei Shinpo, 37(3), 459-467, 1993.
(4) Iyaku Journal, 30(8), 2030-2068, 1994.
(5) DN and P, 5(8), 453-460, 1992.
(6) Annals of Neurology, 30(4), 533-541, 1991.
Compounds poor in the ability to bind to an xcex11 adrenalin receptor are medicines which would scarcely affect blood pressure in orthostatic hypotension, etc. and have a higher safety.
(Reagent)
The following reagents were employed in this test.
1) Serotonin binoxalate (5-HT binoxalate, mfd. by Sigma Chemical Co.).
2) Methysergide maleate (mfd. by RBI).
As radioisotope-labeled compounds, use was made of the following reagents (mfd. by NEN).
3) [3H] 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT).
4) [3H] Ketanserin hydrochloride.
5) [3H] Prazosin.
These compounds and test compounds, when insoluble in water, were dissolved in ethanol and then diluted with distilled water so as to each give an ethanol concentration of 10%. Methysergide maleate was dissolved in distilled water before using.
(Animal)
Use was made of SD rats aged 6 to 8 weeks.
(Preparation of receptor source)
The rats were sacrificed by decapitation to extirpate the cerebra. The hippocampus and cortex were separated therefrom and employed in the binding tests respectively on the serotonin 1A receptor and the serotonin 2 receptor.
The hippocampus was mixed with 50 times (on the wet weight basis) as much a 0.32 M sucrose solution while the cortex was mixed with 10 times as much the same solution. Each mixture was homogenized by using a Teflon glass homogenizer and centrifuged at 1,000xc3x97g for 10 min. The supernatant thus obtained was further centrifuged at 20,000xc3x97g for 20 min. The obtained precipitate was re-suspended in 50 times (based on the initial wet weight; in the case of the hippocampus) or 10 times (in the case of the cortex) as much a 50 mM Tris hydrochloride (pH 7.4) and incubated at room temperature for 30 min. After centrifuging at 20,000xc3x97g for 20 min, the obtained precipitate was further suspended and centrifuged twice each in the same manner. The precipitate thus obtained was suspended in 100 times (based on the initial wet weight; in the case of the hippocampus) or 20 times (in the case of the cortex) as much a 50 mM Tris hydrochloride solution (pH 7.4) to thereby give a receptor fraction. This receptor fraction was stored at xe2x88x9280xc2x0 C. until using.
(Binding test on [3H] 8-hydroxy-dipropylaminotetralin)
To the receptor fraction of the hippocampus were added a test compound and 0.5 nM of [3H] 8-hydroxy-dipropylamino-tetralin and the resultant mixture was incubated at room temperature for 30 min. Next, it was filtered through a glass filter with the use of a cell harvester. After washing the glass filter with 50 mM Tris hydrochloride (pH 7.4), the radioactivity of the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 10 xcexcM of serotonin binoxalate was referred to as the nonspecific binding.
(Binding test on [3H] ketanserin)
To the receptor fraction of the cerebral cortex were added a test compound and 0.3 nM of [3H] ketanserin and the resultant mixture was incubated at 37xc2x0 C. for 15 min. Next, it was filtered through a glass filter with the use of a cell harvester. After washing the glass filter with 50 mM Tris hydrochloride (pH 7.4), the radioactivity of the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 1 xcexcM of methysergide was referred to as the nonspecific binding.
IC50 was calculated by the probit method, while Ki was determined in accordance with the following formula:
Ki=IC50/(1+c/Kd)
wherein c represents the concentration of the radioisotope-labeled compound, and Kd represents the dissociation constant of the radioisotope-labeled compound with respect to the receptor determined by Scatchard""s analysis.
(Binding test on [3H] prazosin)
To the receptor fraction of the cerebral cortex were added a test compound and about 0.2 nM of [3H] prazosin and the resultant mixture was incubated at room temperature for 60 min. Next, it was filtered through a glass filter with the use of a cell harvester. After washing the glass filter with 50 mM Tris hydrochloride (pH 7.4), the radioactivity of the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 10 xcexcM of phentolamine was referred to as the nonspecific binding.
The following tables show the abilities of typical examples of the compounds of the present invention to bind to the serotonin (5HT)1A and serotonin (5HT)2 receptors, wherein the number of each compound corresponds to the number of Example described below. Also, comparison was made with cyproheptadine hydrochloride and cyclobenzaprine hydrochloride which were employed as positive controls having anti-serotonin effects.
Subsequently, the abilities of typical examples of the compounds of the present invention to bind to the xcex11 adrenalin receptor were evaluated by the test method described above. The following table shows the results, wherein the number of each compound corresponds to the number of Example described below.
The above results indicate that the condensed pyridine compound of the present invention are useful as medicaments with a serotonin antagonism and have clinical usefulness and a high safety, in particular, those for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
Moreover, it is also evident that the compounds of the present invention are superior in safety, since they have low abilities to bond to the xcex11 adrenalin receptor and scarcely affect blood pressure.
Next, to illustrate the present invention in detail, Examples will be given below. However, it is needless to say that the present invention is not restricted thereto.